Guidelines: Surrogates vs. Hard Endpoints

In 2007, the cholesterol-lowering drug Zetia (ezetimibe) was a top-selling medication, notching $1.8 billion in sales for Merck and Merck/Schering-Plough.

It probably didn't hurt that Zetia had received a favorable mention when in a 2004 update of cholesterol treatment guidelines -- an update by a nine-member committee, which include seven members with financial ties to the two companies that marketed the drug.

But there was a problem with that advice.

Unlike statins, which demonstrated clinical benefit in the landmark Scandinavian Simvastatin Survival Study (4 S), Zetia had never been shown to reduce heart attacks or strokes. Zetia was approved solely on its cholesterol-lowering ability -- a surrogate endpoint, versus a hard endpoint.

The example is not unique.

Doctors say guidelines may recommend specific drugs, or classes of drugs, because they improve numbers on a blood test, not because they have proven value in decreasing heart attacks, strokes or deaths. While improved blood tests can indicate a health benefit, that is not always the case.

With television advertising, sales boomed for Zetia and Vytorin (a combination of ezetimibe and simvastatin (Zocor)) a second Merck/Schering-Plough drug.

More than $200 million was spent in 2007 on direct-to-consumer ads for Vytorin alone, according to a 2008 article in the New England Journal of Medicine.

The two companies jointly marketed the drugs until, in 2009, Merck merged with Schering-Plough.

Doctors wrote roughly 39 million prescriptions for the two drugs in 2007, according to IMH Health, a market research firm. Combined sales of the two drugs reached $4.3 billion that year, ranking them among the top-selling cholesterol medications.

But in 2008, newly published research suggested the drugs might have no value in improving artery health. Although the trial that found no artery health improvement had ended in April 2006, the results weren't released by the companies until January 2008.

The clinical trial showed now advantage for Vytorin over Zocor alone when judged by carotid intima-media thickness. The companies had hoped to show the statin/Zetia combination in Vytorin further reduced plaque build up in arteries.

In a statement at the time, U.S. Sen. Chuck Grassley (R-Iowa), whose committee investigated the matter, said Merck/Schering-Plough may have deliberately delayed release of the information for marketing purposes.

But Merck/Schering-Plough said unanswered scientific and technical questions caused the delay. After the study came to light, sales fell to $2.3 billion 2011. Company officials maintained the trial results were "blinded" and unknown to the companies and researchers conducting the trial until about two weeks before being released.

Merck spokesman Ronald Rogers said extensive research shows that lowering cholesterol reduces the risk of cardiovascular disease, but many patients can't achieve their cholesterol-lowering goal with just a statin drug. Both Zetia and Vytorin are effective at lowering cholesterol, he said.

Merck now is doing a clinical trial looking at whether Vytorin reduces heart attacks, strokes and deaths, but those results won't be known until 2014.

"Nearly a dozen years after the drug was approved we still won't have any idea whether it's beneficial or not," said Sanjay Kaul, MD, a Los Angeles cardiologist who has served on U.S. Food and Drug Administration advisory panels. "That's obviously a problem in the system. The fact that over $21 billion dollars of Zetia has been sold in the last decade speaks more to the miracle of marketing than to the miracle of medicine."

In an email, guideline panel member Scott Grundy, MD, a professor of internal medicine and a cholesterol expert at the University of Texas Southwestern, acknowledged there was no proof at the time that Zetia reduced heart attacks or strokes -- what doctors often refer to as clinical benefit.

The FDA approved Zetia because it was good at lowering cholesterol and because there was no evidence of harm, said Grundy, who was lead author of the 2004 group that updated the cholesterol guideline and recommended Zetia.

At the time, Grundy reported getting honoraria from Merck, Merck/Schering-Plough and several other drug companies. He said his financial relationship with Merck and Merck/Schering-Plough did not influence his work on the panel.

"No, I did not contribute to guideline development in hopes that it would make the shareholders of drug company stock rich," he wrote in an email.

Doctors who study the issue argue that while research on a drug done to get FDA approval may not show harm, that does not mean problems don't arise when the drugs gain widespread use.

In the case of Zetia and Vytorin, a 2008 study in the New England Journal of Medicine found indications of a potentially dangerous shift in prescriptions.

Between 2002 and 2008, prescriptions for statin drugs declined as prescriptions soared for Zetia and Vytorin -- which have no proven clinical benefit.

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